Recent research has shown that a multidiscipline approach to cancer combining hyperthermia (elevated temperature), chemotherapy and immunotherapy can produce striking responses in patients with cancers confined to the limbs. The limitation of this approach resides in the fact that most cancers resistant to therapy ultimately involve the entire body. The initial rationale for combining immunotherapy [e.g., tumor necrosis factor (TNF) and interferon] with hyperthermia and a chemotherapeutic drug [i.e., melphalan (L-PAM)] in limb studies was not entirely grounded on a firm scientific foundation. Thus, it was not clear how these forms of therapy should be safely combined in order to optimally treat a patient's entire body. Treating the whole patient is generally necessary to cure an individual (as opposed to just treating local disease, which may only address quality of life issues). In order to address the issue of the optimal sequencing and dosing of hyperthermia, immunotherapy and melphalan, a laboratory program was initiated at the University of Wisconsin Comprehensive Cancer Center (UWCCC). The results of this research have provided invaluable insights into the optimization of this combination; these investigations are consistent with translation of laboratory data obtained to clinical trials involving patients with cancer. Based on these preclinical studies a phase I clinical trial of whole body hyperthermia (WBH) and melphalan was recently completed at the UWCCC/GCRC. The results of this trial are consistent with the safety and efficacy of this combination. We now propose to further extend our laboratory results to a second generation trial. The overall goal of this project will be to maximize cancer destruction while minimizing side effects, by combining whole body hyperthermia with immunotherapy and chemotherapy. It is anticipated that three forms of cancer, i.e., malignant melanoma, sarcoma, and lymphoma, may be uniquely suited to such multi-modality therapy. Inherent in these investigations will be ancillary research which serves to refine and improve therapy by clarifying underlying biological mechanisms.